Highly Potent Compounds

6 mins 22/11/20
Author name: John Ross

Navigating Highly Potent Manufacturing Requirements

The pharmaceutical industry’s drive to improve patient health by developing more effective medicinal products is seeing many of its drug developers turning to highly potent active pharmaceutical ingredients (HPAPIs), particularly in oncology.

Higher potencies typically mean only small doses are required in finished drugs; and, as in the case of antibody-drug conjugates, which carry the API directly to the treatment site, they can avoid some of the side effects associated with conventional treatments.

Yet high potency creates a huge challenge for manufacturers: safety. Paired with a changing regulatory environment, this challenge often sees pharmaceutical companies turn to full-service specialist partners which can think strategically about their product’s journey from laboratory to market.

The regulatory challenges

Regulatory controls concerning HPAPI manufacturing have grown more robust; companies are now being asked to rely on engineering controls rather than on standard work practices and personal protective equipment to reduce workers’ exposure to HPAPIs.

Regulations and guidance covering HPAPIs often have similar themes relating to containment, cleaning, and handling, the number of disparate requirements and subtle difference can also pose significant challenges for a manufacturer.

  • Occupational Health and Safety Management System (OHSMS) 18001 and ISO 14001 set out clear worker safety and environmental health standards for HPAPI processing.
  • S. and European current Good Manufacturing Practice (cGMP) guidelines also cover HPAPIs, detailing how manufacturers should try to avoid cross-contamination, clean equipment, and handle various substances[1][2].
  • FDA guidance on aseptic processing also incorporates HPAPI handling in sections covering the containment of ingredients during manufacture[3]
  • The International Council for Harmonization (ICH) document on quality systems, ICH Q106 also offers guidance on HPAPI handling.
  • A number of International Organization for Standardization (ISO) standards pertain to HPAPIs including ISO 13408 on aseptic processing; ISO 14664-1 on cleanrooms and controlled environments; and ISO 11134, 11137, and 14937 on sterilization.

Regulators worldwide have also placed increased focus mitigating cross-contamination and ensuring proper facility design for multi-product operations processing HPAPIs. This, in turn, has given rise to additional cleaning and validation requirements, in response many companies are exploring single-use technologies and systems which promise more efficient turnaround and remove the need to clean certain components.

Environmental considerations

While environmental agencies were initially slow to act, there is now a focus from bodies such as the US Environmental Protection Agency on ensuring HPAPIs are managed in process wastewater systems with established performance-based limits using ecotoxicology data for HPAPIs. Such development aspects require significant investment and affect business terms for installing and providing services for HPAPI drug products.

Managing risk

Entering the HPAPI market is not for the inexperienced or those of limited funds, as evidenced by the growing propensity to outsource these capabilities. Pharmaceutical companies considering whether to add in-house HPAPI manufacturing capabilities must be prepared to invest substantially in remediating or retrofitting uncontained equipment and sites for legacy products to comply with current regulations governing the safe handling of HPAPIs.

The industry has access to a wide range of containment solutions at various cost points that accommodate many unit operations and scales (discovery, laboratory, commercial manufacturing, and packaging). As each year brings new innovations, developments and lower technology costs, the capital expenditure required by a company to manufacture HPAPIs in-house lowers, bringing one of the barriers to market entry with it. However, companies will still have to balance investment strategies for equipment and infrastructure against the potential business opportunities available to them.

The investment is not just in equipment either, upskilling personnel is an essential part of effective HPAPI handling. Although the availability of a wide variety of containment technologies and equipment, such as split butterfly valves, isolators, and bag-in/bag-out filters, is encouraging, merely installing any number or combination of these in itself is insufficient. A credible CDMO will ensure all workers can confidently use them and fully comprehend the hazards. Furthermore, their staff training isn’t limited to machinery; it also encompasses best practices in handling HPAPIs.

Outsourcing naturally transfers the majority of risk, resource investment, and material handling complexity onto the contract partner. Each company has its own reasons for outsourcing HPAPI handling and processing, but they generally encompass risk management, misalignment of production scale or facility utilization dynamics, and availability of up-to-date approaches to HPAPI controls.

Choosing a HPAPI partner

Many contract development and manufacturing organizations (CDMOs) offer HPAPI capabilities, which serves only to make the selection process more complicated. Large contract manufacturing organizations (CMOs), with their high production volumes, may seem like the obvious choice, but given the smaller dosage-unit volumes of HPAPIs, more and more companies are opting for smaller scale specialist partners, such as Metrics Contract Services. This smaller scale is not to be overlooked — it is a key component of risk mitigation given the cost of many HPAPIs.

Companies seeking guidance on their potent product stand to benefit by outsourcing, providing they find the appropriate partner. Services on offer vary greatly between CDMOs, with some only interested in larger-scale manufacturing work whereas specialized partners can be more invested in a product’s success, working hard to troubleshoot and fast track drug development.

Before embarking on a project and introducing a new product into a facility, a certified toxicologist or industrial hygienist should properly categorize and control-band each HPAPI according to its hazards. This helps to not only determine the optimal level of containment investment needed for the HPAPI, but also whether the partner has the capabilities to deliver the work.

At an early development stage it is strongly advisable to use a certified toxicologist to obtain OEL (occupational exposure limits) and acceptable daily exposure values as these will help in selecting appropriate containment equipment as well as promoting safe handling and processing of HPAPIs.

Metrics Contract Services

Given the challenges of HPAPI handling and the potential health and safety hazards, it is essential that your chosen partner has the proper equipment, facilities, and infrastructure, including trace elements testing, to handle HPAPIs. The CDMO must be fully versed in the numerous risks associated with different unit operations and scales and be able to articulate a suitable plan to mitigate those risks.

Metrics Contract Services can provide full support from formulation development and analytical services right through to the clinical stages and commercial manufacturing is essential. Thinking holistically about a drug’s lifecycle will ensure manufacturability and downstream success.


[1] http://www.ecfr.gov/cgi-bin/text-idx?SID=3ee286332416f26a91d9e6d786a604ab&mc=true&tpl=/ecfrbrowse/Title21/21tab_02.tpl

[2] http://ec.europa.eu/health/files/eudralex/vol-4/chapter_5.pdf

[3] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice